Whole blood clot formation phenotypes in hemophilia A and rare coagulation disorders. Patterns of response to recombinant factor VIIa

Abstract

Summary. Until now, no routinely used clotting assay has demonstrated the power to re¯ect signi®cantly a patient's response to recombinant factor (rF)VIIa. Adopting a thrombelastographic principle, pro®les of continuous whole blood (WB) coagulation were studied in minimally altered WB activated with a small amount of tissue factor (TF). Investigation of the WB clotting pro®le was performed before and after ex vivo addition of rFVIIa 20 nM to WB from 26 patients with hemophilia A, two patients with severe hemophilia B, and individuals with de®ciencies of FV, FX, FXI, and FXIII. In ®ve patients with hemophilia plus inhibitors, the response to ex vivo added rFVIIa and to activated complex concentrate (APCC) was studied. Patients with severe and moderate hemophilia A demonstrated remarkable variance in the hemostatic characteristics at baseline, even in groups with the same FVIII:C activity levels. The response to rFVIIa at 20 nM also varied extensively, the effect correlating with the continuous WB coagulation phenotype at baseline. This indicates that the ef®cacy of rFVIIa may be optimized by tailoring the dose according to the hemostatic response to varying doses tested prior to in vivo administration. In patients with inhibitors against FVIII and factor IX, rFVIIa and APCC substitution resulted in quite similar response patterns that appeared to be dose dependent. In severe FV, FX, and FXIII-de®cient WB, rFVIIa addition induced minor changes only. In FXI de®ciency, rFVIIa normalized the dynamic properties of clotting, although a reduced clot ®rmness remained unchanged. In conclusion, the thrombelastographic analysis of WB clotting, as activated with a minute amount of TF, seems an interesting method that detects phenotypic variation amongst hemophilia patients. The method appears useful for assessment of the hemostatic capacity and it seems a promising tool for evaluation of the individual response to rFVIIa or APCC before and during in vivo administration.

Monitoring Recombinant Factor VIIa Treatment: Efficacy Depends on High Levels of Fibrinogen in a Model of Severe Dilutional Coagulopathy

“…[6][7][8] In theses studies, thrombelastography/thrombelastometry seems to be a promising methods for characterization of phenotypic variance amongst patients as well as in detection of the individual response to rFVIIa prior and following rFVIIa administration. Presence of high amounts of tissue factor may directly activate the coagulation cascade (bypassing agent) and effects of rFVIIa may no longer be monitored.…”

“…Both technologies have been described in detail elsewhere. 21,22 Briefly, the measurements are based on the detection 7 of viscoelastic changes of a blood sample after activation with different coagulation activators (1:1,000 diluted tissue factor was used for this study).…”

“…5 Viscoelastic techniques like thrombelastography/thrombelastometry or Sonoclot analysis appear to be highly desirable and have shown some promising results. [6][7][8] Coagulation is assessed in whole blood allowing coagulation factors to interact with red cells and platelets. rFVIIa increases thrombin formation by tissue factor dependent and -independent activation of factor X on the surface of platelets.…”

Evaluation of coagulation kinetics using thromboelastometry—methodologic influence of activator and test medium

“…During the past decade, renewed interest has arisen in the use of thromboelastography or thromboelastometry for evaluation of coagulation kinetics [1][2][3][4][5][6][7][8][9][10][11][12]. These viscoelastic analyses benefit by providing a continuous visualization of physical changes occurring during blood coagulation.…”

Aptamer ARC19499 mediates a procoagulant hemostatic effect by inhibiting tissue factor pathway inhibitor

“…26 Like the CAT assay, it is used to measure the hemostatic response of hemophilic whole blood or plasma, 27,28 and is currently under intense study as a monitoring method to guide the dosing of bypass agents such as activated prothrombin complex concentrates and recombinant FVIIa. 27,29 To assess the effect of ARC19499 on clot formation in whole blood, FVIII-depleted whole blood was prepared using an inhibitory, anti-FVIII polyclonal antibody. Increasing ARC19499 concentrations were tested in both untreated and antibody-treated whole blood using the TEG assay, with clotting initiated by the addition of TF and CaCl 2 ( Figure 5).…”